New functionalised silicas for highly selective cation exchange SPE purification in medicinal chemistry

Functionalised silicas 2 and 3 are effective for the cation exchange SPE purification of basic molecules containing acid-sensitive functionalities, the selective separations of mixtures of basic compounds and accelerated reaction work-ups/product isolations.     

A protecting group free synthesis of (+/-)-neostenine via the [5 + 2] photocycloaddition of maleimides

A concise, linear synthesis of the Stemona alkaloid (+/-)-neostenine is reported. Key features include an organocopper-mediated bislactone C2-desymmetrization for the stereoselective construction of the cyclohexane-lactone C,D-rings. The assembly of the fused pyrrolo[1,2-a]azepine core was achieved by application of a [5 + 2] maleimide photocycloaddition. A custom FEP flow reactor was used to successfully overcome the scale limitations imposed by a classical immersion well batch reactor. The synthesis was completed in 14 steps from furan, in 9.5% overall yield, without the use of any protecting groups.     

Derived sequences and reverse mathematics

One of the earliest applications of transfinite numbers is in the construction of derived sequences by Cantor [2]. In [6], the existence of derived sequences for countable closed sets is proved in ATR₀. This existence theorem is an intermediate step in a proof that a statement concerning topological comparability is equivalent to ATR₀. In actuality, the full strength of ATR₀ is used in proving the existence theorem. To show this, we will derive a statement known to be equivalent to ATR₀, using only RCA₀ and the assertion that every countable closed set has a derived sequence. We will use three of the subsystems of second order arithmetic defined by H. Friedman ([3], [4]), which can be roughly characterized by the strength of their set comprehension axioms. RCA₀ includes comprehension for Δ definable sets, ACA₀ includes comprehension for arithmetical sets, and ATR₀ appends to ACA₀ a comprehension scheme for sets defined by transfinite recursion on arithmetical formulas. MSC: 03F35, 54B99.     

A Self‐Assembled Respiratory Chain that Catalyzes NADH Oxidation by Ubiquinone‐10 Cycling between Complex I and the Alternative Oxidase

Complex I is a crucial respiratory enzyme that conserves the energy from NADH oxidation by ubiquinone‐10 (Q₁₀) in proton transport across a membrane. Studies of its energy transduction mechanism are hindered by the extreme hydrophobicity of Q₁₀, and they have so far relied on native membranes with many components or on hydrophilic Q₁₀ analogues that partition into membranes and undergo side reactions. Herein, we present a self‐assembled system without these limitations: proteoliposomes containing mammalian complex I, Q₁₀, and a quinol oxidase (the alternative oxidase, AOX) to recycle Q₁₀H₂ to Q₁₀. AOX is present in excess, so complex I is completely rate determining and the Q₁₀ pool is kept oxidized under steady‐state catalysis. The system was used to measure a fully‐defined K_M value for Q₁₀. The strategy is suitable for any enzyme with a hydrophobic quinone/quinol substrate, and could be used to characterize hydrophobic inhibitors with potential applications as pharmaceuticals, pesticides, or fungicides.     

Self‐Assembly of Two‐Component Gels: Stoichiometric Control and Component Selection

Two‐component systems capable of self‐assembling into soft gel‐phase materials are of considerable interest due to their tunability and versatility. This paper investigates two‐component gels based on a combination of a L ‐lysine‐based dendron and a rigid diamine spacer (1,4‐diaminobenzene or 1,4‐diaminocyclohexane). The networked gelator was investigated using thermal measurements, circular dichroism, NMR spectroscopy and small angle neutron scattering (SANS) giving insight into the macroscopic properties, nanostructure and molecular‐scale organisation. Surprisingly, all of these techniques confirmed that irrespective of the molar ratio of the components employed, the “solid‐like” gel network always consisted of a 1:1 mixture of dendron/diamine. Additionally, the gel network was able to tolerate a significant excess of diamine in the “liquid‐like” phase before being disrupted. In the light of this observation, we investigated the ability of the gel network structure to evolve from mixtures of different aromatic diamines present in excess. We found that these two‐component gels assembled in a component‐selective manner, with the dendron preferentially recognising 1,4‐diaminobenzene (>70 %), when similar competitor diamines (1,2‐ and 1,3‐diaminobenzene) are present. Furthermore, NMR relaxation measurements demonstrated that the gel based on 1,4‐diaminobenzene was better able to form a selective ternary complex with pyrene than the gel based on 1,4‐diaminocyclohexane, indicative of controlled and selective π–π interactions within a three‐component assembly. As such, the results in this paper demonstrate how component selection processes in two‐component gel systems can control hierarchical self‐assembly.     

Resonant scattering from liquid crystal devices: an in-situ structural probe for the smectic phases

Resonant X-ray scattering is a relatively new technique in the field of liquid crystals and in recent years has been used to investigate the structures of the SmC* sub-phases. This work has been carried out on several materials which include either a sulfur or selenium atom and has revealed the detailed biaxial structure of the four layer intermediate (ferrielectric) phase. Resonant X-ray scattering has also been used to produce the first in-situ measurements of the chiral smectic sub-phases in a liquid crystal device. Both the antiferroelectric and the four-layer intermediate phases have been observed via this technique in a device geometry. Electric field studies have also been carried out in these phases whilst monitoring phase structure simultaneously. In this paper I will summarize the most up-to-date results from resonant scattering in free-standing films and discuss resonant scattering experiments on liquid crystal devices.     

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Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide ‘tail’ to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q ² value of 0.85 and a r ² of 0.94. Results from the docking simulations and the interpretation from QSAR “coeff*stdev” contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.     

Ab initio potential energy surfaces, bound states, and electronic spectrum of the Ar-SH complex

New ab initio potential energy surfaces for the (2)Pi ground electronic state of the Ar-SH complex are presented, calculated at the RCCSD(T)/aug-cc-pV5Z level. Weakly bound rotation-vibration levels are calculated using coupled-channel methods that properly account for the coupling between the two electronic states. The resulting wave functions are analyzed and a new adiabatic approximation including spin-orbit coupling is proposed. The ground-state wave functions are combined with those obtained for the excited (2)Sigma(+) state [D. M. Hirst, R. J. Doyle, and S. R. Mackenzie, Phys. Chem. Chem. Phys. 6, 5463 (2004)] to produce transition dipole moments. Modeling the transition intensities as a combination of these dipole moments and calculated lifetime values [A. B. McCoy, J. Chem. Phys. 109, 170 (1998)] leads to a good representation of the experimental fluorescence excitation spectrum [M.-C. Yang, A. P. Salzberg, B.-C. Chang, C. C. Carter, and T. A. Miller, J. Chem. Phys. 98, 4301 (1993)].